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AG Stange

 

Gastro-intestinal stem cell and cancer biology 

Research Focus

Our group is interested in the mechanisms underlying epithelial regeneration and cancer development in the gastro-intestinal tract. We try to understand the mechanisms by which adult stem cells maintain homeostasis within the tissue, but also how they react upon challenges like inflammation, and how dysregulation of stem cell homeostasis initiates tumor growth.  

BackgroundOrganoid

Intestinal stem cells have been first identified by the laboratory of Hans Clevers by a specific marker (Lgr5) which is uniquely expressed in this cell type (1). The identification of the intestinal stem cell marker Lgr5 has allowed a detailed molecular analysis of the intestinal stem cell, resulting in the definition of the intestinal stem cell signature (2). Several stem cell specific genes have subsequently been shown to be important players in the maintenance of intestinal stem cell homeostasis, such as Ascl2 (3), Lrig1 (4) and Rnf43 (5). A mouse model expressing a fluorescent mark under the promoter of one of these stem cell signature genes, i.e. Troy, identified several Troy positive cell populations in different organs of the mouse, including a population of cells at the bottom of gastric glands (6). Lineage tracing experiments proved the stemness of this cell population, which was termed due to its slow cycling nature a reserve stem cell of the gastric epithelium. In parallel, culture conditions were developed that allowed an outgrowth of single Troy positive cells into so-called organoids: small organ-like 3D structures that contain stem cells and differentiated cells of the organ of origin (7). Variation of culture conditions has also allowed the outgrowth of human intestinal tissue, including from colon cancer (8). Subsequently, we have established a biobank of stomach cancer organoids that recapitulates in vitro the different phenotypes, genotypes and response towards chemotherapeutics as well as targeted drug treatments of in vivo gastric cancer (9). Currently, we have set up co-clinical trials in which we evaluate the power of patient-derived cancer organoids to predict therapy response. In parallel, we developed mouse models to recapitulate different known subtypes of gastric cancer (10). These different mouse models faithfully recapitulate features of known human gastric cancer subtypes. Different combinations of oncogenic allels resulted in tumors of different stages of cancer development, from initial dysplasia to metastatic cancer.

Our work has established in vitro and in vivo model systems of gastric cancer that in the future will allows us to answer questions concerning stomach cancer initiation and progression. In parallel, we evaluate in different settings how patient-derived organoids can be used to help clinical decision making. 

Our laboratory focuses on three main topics

  • Gastric stem cells in homeostasis, inflammation and tumor initiation/progression.
  • Optimizing gastric cancer treatment by the use of patient-derived cancer organoids.
  • Genetic manipulation of organoids to unravel the function of frequently mutated cancer genes.

To approach these questions we are using state of the art technologies such as genetically modified mice and organoids. Furthermore, close collaborations with groups from the Medical Faculty , the Max Planck Institute  and the Center for Regenerative Diseases (CRTD) exist, connecting adult stem cell research on the campus. We have furthermore access to diverse core facilities, including an advanced microscopy, mouse transgenic and NGS core facility. Internationally, we are collaborating with groups at the IMBA in Vienna, the Cambridge Stem Cell Institute, the CNIO in Madrid, the Baylor College of Medicine in Houston and the McGill University in Montreal.

(1) Barker et al, Nature, 2005 (2) Munoz*, Stange* et al, EMBO, 2012  (3) van der Flier et al, Cell, 2009 (4) Wong*, Stange* et al, Nat Cell Biol, 2012 (5) Koo et al, Nature, 2012 (6) Stange*, Koo* et al, Cell, 2013 (7) Sato et al, Nature, 2009 (8) Sato et al, Gastroenterology, 2011 (9) Seidlitz et al, Gut, 2019 (10) Seidlitz et al, Gastroenterology, 2019

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